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J. Biol. Chem., Vol. 282, Issue 52, 37370-37377, December 28, 2007

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Protein Kinase A, not Epac, Suppresses Hedgehog Activity and Regulates Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia Cells^*

Zhenyu Ji¹, Fang C. Mei, Betty H. Johnson, E. Brad Thompson², and Xiaodong Cheng³

From the Departments of Pharmacology and Toxicology and Biochemistry and Molecular Biology, School of Medicine, The University of Texas Medical Branch, Galveston, Texas 77555

Cyclic AMP synergizes strongly with glucocorticoids (GC) to induce apoptosis in normal or malignant lymphoid cells. We examined the individual roles that cAMP-dependent protein kinase (PKA) and Epac (exchange protein directly activated by cAMP), two intracellular cAMP receptors, play in this synergistic effect. Our studies demonstrate that PKA is responsible for the observed synergism with GC, whereas Epac exerts a weak antagonistic effect against GC-induced apoptosis. We find that endogenous PKA activity is higher in the GC-sensitive clone than in the GC-resistant clone. In the GC-sensitive clone, higher PKA activity is associated with lower Hedgehog (Hh) activity. Moreover, inhibition of Hh activity by Hh pathway-specific inhibitors leads to cell cycle arrest and apoptosis in CEM (human acute lymphoblastic leukemia, T lineage) cells, and the GC-sensitive clone is more sensitive to Hh inhibition. These results suggest that Hh activity is critical for leukemia cell growth and survival and that the level of Hh activity is in part responsible for the synergism between cAMP and GC.

Received for publication, May 4, 2007 , and in revised form, September 25, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a training fellowship from the Pharmacoinformatics Training Program of the Keck Center of the Gulf Coast Consortia under National Institutes of Health Grants 1 T90 DK070109-01 and 1 R90 DK071505-01.

² Supported by Public Health Service Grant CA041407 from the National Cancer Institute.

³ Supported by Public Health Service Grant GM066170 from the National Institute of General Medical Sciences, by Grant-in-Aid 0755049Y from the American Heart Association, and in part by Center Grant ES06676 from the NIEHS, National Institutes of Health. To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031. Tel.: 409-772-9656; Fax: 409-772-9642; E-mail: xcheng{at}utmb.edu.

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